Alemtuzumab
 | |
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Humanized (from rat) |
| Target | CD52 |
| Clinical data | |
| Trade names | Campath |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a608053 |
| Pregnancy category |
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| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Elimination half-life | ~288 hrs |
| Identifiers | |
| CAS Number | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C6468H10066N1732O2005S40 |
| Molar mass | 145453.8 g/mol g·mol−1 |
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Alemtuzumab (marketed as Campath, MabCampath or Campath-1H and currently under further development as Lemtrada) is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It is also used in some conditioning regimens for bone marrow transplantation, kidney transplantation and Islet cell transplantation.
Alemtuzumab binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction.
Alemtuzumab is used as second-line therapy for CLL. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. It has been approved by Health Canada for the same indication, and additionally for CLL patients who have not had any previous therapies.
It is also used under clinical trial protocols for treatment of some autoimmune diseases, such as multiple sclerosis, in which it shows promise.[2][3] Alemtuzumab was withdrawn from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch aimed at multiple sclerosis.[4]
A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus.
Description
Alemtuzumab (Campath-1H) is a recombinant DNA-derived humanized monoclonal antibody that is directed against the 21–28 kDa cell surface glycoprotein CD52.
Indications and use
Alemtuzumab is indicated for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. It is an unconjugated antibody, thought to work via the activation of antibody-dependent cell-mediated cytotoxicity(ADCC).[5]
Sanofi acquisition and change of license controversy
In February 2011, Sanofi-Aventis, since renamed Sanofi, acquired Genzyme, the manufacturer of alemtuzumab.[6] The acquisition was delayed by a dispute between the two companies regarding the value of alemtuzumab. The dispute was settled by the issuance of Contingent Value Rights, a type of stock warrant which pays a dividend only if alemtuzumab reaches certain sales targets. The warrants trade on the NASDAQ-GM market with the ticker symbol GCVRZ.
In August 2012, Genzyme surrendered the licence for all presentations of alemtuzumab,[7] pending regulatory approval to re-introduce it as a treatment for multiple sclerosis. There is concern[8] that Genzyme will later bring to market the same product at a much higher price than before.
Research or off-label use
Multiple sclerosis
In 2008 early tests at Cambridge University suggest that alemtuzumab might be useful in treating and even reversing the effects of multiple sclerosis.[9] Promising results were reported in 2011 from a phase III trial against Rebif. A combination trial with Copaxone is being considered, and is expected to work synergistically.[3]
Graft-versus-host disease
A 2009 study of alemtuzumab in 20 patients with severe steroid-resistant acute intestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT) demonstrated improvement. Overall response rate was 70%, with complete response in 35%. In this study, the median survival was 280 days. Important complications following this treatment included cytomegalovirus reactivation, bacterial infection, and invasive aspergillosis infection.[10]
Contraindications and precautions
Alemtuzumab is contraindicated in patients who have active systemic infections, underlying immunodeficiency (e.g., seropositive for HIV), or known Type I hypersensitivity or anaphylactic reactions to Campath or to any one of its components.
Adverse reactions
Alemtuzumab has been associated with infusion-related events including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash. In post-marketing reports, the following serious infusion-related events were reported: syncope, pulmonary infiltrates, ARDS, respiratory arrest, cardiac arrhythmias, myocardial infarction and cardiac arrest. The cardiac adverse events have resulted in death in some cases.[citation needed]
It is also possible that perturbation of suppressor T cell populations by Campath-1H may precipitate autoimmune disease.[citation needed]
History
The origins of alemtuzumab date back to Campath-1 which was derived from the rat antibodies raised against human lymphocyte proteins by Herman Waldmann and colleagues in 1983.[11] The name "Campath" derives from the pathology department of Cambridge University.
Initially, Campath-1 was not ideal for therapy because patients could, in theory, react against the foreign rat protein determinants of the antibody. To circumvent this problem, Greg Winter and his colleagues humanised Campath-1, by extracting the hypervariable loops that had specificity for CD52 and grafting them onto a human antibody framework. This became known as Campath-1H and serves as the basis for alemtuzumab.[12]
Campath as medication was first approved in 2001. It is marketed by Genzyme, which acquired the world-wide rights from Bayer AG in 2009. Genzyme was bought by Sanofi in 2011. In August/September 2012 Campath was withdrawn from the markets in the US and Europe. This was done to prevent off-label use of the drug to treat multiple sclerosis and to prepare for a relaunch under the trade name Lemtrada, with a different dosage aimed at multiple sclerosis treatment, this is expected to be much higher-priced.[4]
References
- ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
- ^ "Drug may reverse MS brain damage". 22 Oct 2008.
- ^ a b "Sanofi and Genzyme Report New Positive Data from First Phase III Study with MS Drug". 24 Oct 2011.
- ^ a b "Sanofi withdraws Campath in US and EU". Pharma Times Online. August 21, 2012.
- ^ http://www.campath.com/hcp/AboutCampath.html
- ^ "Sanofi Buys Genzyme for over $20 billion". Retrieved 9 January 2013.
- ^ "Discontinuation of licensed supplies of alemtuzumab (Mabcampath)". national electronic Library for Medicines. Retrieved 1 November 2012.
- ^ "Multiple sclerosis: New drug 'most effective'". BBC News. 1 November 2012. Retrieved 1 November 2012.
- ^ Drug reboots immune system to reverse MS, Andy Coghlan, New Scientist News Service, October 23, 2008.
- ^ Successful treatment of severe acute intestinal graft-versus-host resistant to systemic and topical steroids with alemtuzumab., Schnitzler M, Biol Blood Marrow Transplant. 2009 Aug;15(8):910-8.
- ^ Hale G, Bright S, Chumbley G, Hoang T, Metcalf D, Munro AJ, Waldmann H. Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood 1983;62:873-82. PMID 6349718.
- ^ Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature 1988;332:323-7. doi:10.1038/332323a0 PMID 3127726.